Safety Study of Pyridostigmine in Heart Failure (APP-HF)

• Resting Heart Rate Variability [ Time Frame: Times 0 (pre-randomization), 8 weeks, 12 weeks ] [ Designated as safety issue: No ]
  Time- and Frequency-domain assessment of sympathovagal balance
• Cardiovagal baroreceptor function [ Time Frame: Times 0 (pre-randomization), 8 weeks, 12 weeks ] [ Designated as safety issue: No ]
  Changes in heart rate and blood pressure in response to application of neck suction/pressure
• Kansas City Cardiomyopathy Questionnaire [ Time Frame: Times 0 (pre-randomization), 8 weeks, 12 weeks ] [ Designated as safety issue: No ]
  Validated Quality of Life questionnaire
• Cholinergic Symptom Score [ Time Frame: Every 1-2 weeks for 12 weeks ] [ Designated as safety issue: Yes ]
  Validated questionnaire on cholinergic side effects
• Spirometry [ Time Frame: Every 1-2 weeks for 12 weeks ] [ Designated as safety issue: Yes ]
  measure of lung function
• Electrocardiogram [ Time Frame: Every 1-2 weeks for 12 weeks ] [ Designated as safety issue: Yes ]
  12-lead EKG

Heart failure, a common heart disease affecting nearly 6 million Americans, is associated with high rates of hospitalization and death. Abnormalities in the autonomic nervous system are thought to play an important role in the progression of heart failure. This proposal aims to determine whether novel application of pyridostigmine, a drug currently approved by the FDA only for the treatment of neuromuscular disease, can improve autonomic nervous system function in heart failure patients.

Autonomic dysregulation of the cardiovascular system, characterized by heightened sympathetic activity and withdrawal of parasympathetic activity promotes progression of heart failure. Pharmacological blockade of sympathetic overactivity is associated with reduced mortality risk, but there are few data on pharmacologic augmentation of parasympathetic withdrawal. Acetylcholinesterase inhibitors augment parasympathetic neurotransmission by blocking the enzymatic breakdown of acetylcholine at cholinergic receptor sites. Pyridostigmine is a short-acting, reversible acetylcholinesterase inhibitor approved by the FDA for the treatment of myasthenia gravis. We now propose a Phase II prospective randomized, double-blind trial to compare 12 weeks of treatment with ascending doses of pyridostigmine (15, 30, and 60 mg every 8 hours) vs. matching placebo in 60 patients with symptomatic chronic heart failure associated with left ventricular systolic dysfunction. The clinical pharmacology of pyridostigmine will be investigated for each of the following specific aims: 1) To characterize the effects of oral pyridostigmine vs. placebo on sympathovagal balance in patients with chronic heart failure; 2) To characterize the safety and tolerability of oral pyridostigmine vs. placebo in patients with chronic heart failure; and 3) To characterize the steady state pharmacokinetic and pharmacodynamic properties of repeated oral dosing of pyridostigmine in patients with chronic heart failure. Mixed effects models will be used to determine the association between study drug assignment and physiological markers of sympathovagal balance (post-exercise heart rate recovery, heart rate variability, cardiovagal baroreceptor function, and rest/exercise blood catecholamine levels), descriptive statistics to characterize safety/tolerability measures (exercise capacity, quality of life, biomarkers of disease progression, cholinergic symptoms score), and population pharmacokinetic/pharmacodynamic modeling to characterize the relationship between study dosing, study drug blood levels, the degree of cholinesterase inhibition and the measures of sympathovagal balance and safety/tolerability. The overall goal is to further characterize the potential of pyridostigmine as a novel treatment in heart failure subjects and obtain information necessary to evaluate the feasibility/logistics of a future Phase III outcomes study in heart failure patients. The proposed studies will provide new data that are critically needed to direct the future development of this promising drug as a novel therapeutic approach for reduction of morbidity and mortality in heart failure patients.

• Experimental: Pyridostigmine Bromide
  Forced titration protocol 15-60 mg every 8 hours as tolerated
  Intervention: Drug: Pyridostigmine Bromide
• Placebo Comparator: Placebo
  Matching placebo forced titration 15-60 mg as tolerated
  Intervention: Drug: Pyridostigmine Bromide

Inclusion Criteria:

• Age 21-75 years
• Symptomatic NYHA Class II-III heart failure >6 months
• Left ventricular ejection fraction <35%
• Previous implantation of implantable cardiovertor defibrillator or pacemaker
• Guideline-recommended heart failure treatment for > 3 months
• Able and willing to provide written informed consent

Exclusion Criteria:

• Contraindications to cholinergic stimulation
• Heart failure primarily attributable to genetic, valvular, infiltrative diseases
• Persistent atrial fibrillation
• Sick sinus syndrome
• Pacemaker dependency during exercise
• Severe chronotropic incompetence with peak exercise heart rate < 100 min-1
• Severe exercise intolerance (unable to complete first stage of Bruce Protocol)
• Coronary or cerebral atherothrombotic events within the past year
• Hospitalization of emergency room visit for heart failure within last 3 months
• ICD shock in last 6 months
• Diabetes mellitus with peripheral neuropathy
• Autonomic or peripheral neuropathy of any cause
• Systolic blood pressure <90 or >160 mmHg
• Resting heart rate <60 or >100 min-1
• Serum sodium < 132 mmol/L
• Serum creatinine >2.5 mg/dl
• Liver function tests >3 times upper limit of normal
• Severe anemia (Hemoglobin <10 gm/dl)
• FEV1.0 < 60% of predicted or FEV1.0/FVC ratio <70%
• PR interval >240 msec or second or third degree heart block on electrocardiogram
• Exercise limited primarily by angina or non-cardiac co-morbid condition
• Pregnant or breast-feeding women
• Current treatment with medications known to interact with pyridostigmine
• Known intolerance of oral preparations containing bromides
• Any condition (e.g., psychiatric illness or active substance abuse) or situation that, in the investigator's opinion, may put the subject at significant risk, may confound the study results, or may interfere significantly with the subject's ability to adhere with study procedures.

• Nathan Kline Institute for Psychiatric Research
• Oklahoma State University
• National Heart, Lung, and Blood Institute (NHLBI)